An update on the development of antiviral against Mayaro virus: from molecules to potential viral targets

Abstract

Mayaro virus (MAYV), first isolated in 1954 in Trinidad and Tobago islands, is the causative agent of Mayaro fever, a disease characterized by fever, rashes, headaches, myalgia, and arthralgia. The infection can progress to a chronic condition in over 50% of cases, with persistent arthralgia, which can lead to the disability of the infected individuals. MAYV is mainly transmitted through the bite of the female Haemagogus spp. mosquito genus. However, studies demonstrate that Aedes aegypti is also a vector, contributing to the spread of MAYV beyond endemic areas, given the vast geographical distribution of the mosquito. Besides, the similarity of antigenic sites with other Alphavirus complicates the diagnoses of MAYV, contributing to underreporting of the disease. Nowadays, there are no antiviral drugs available to treat infected patients, being the clinical management based on analgesics and non-steroidal anti-inflammatory drugs. In this context, this review aims to summarize compounds that have demonstrated antiviral activity against MAYV in vitro, as well as discuss the potentiality of viral proteins as targets for the development of antiviral drugs against MAYV. Finally, through rationalization of the data presented herein, we wish to encourage further research encompassing these compounds as potential anti-MAYV drug candidates.

Keywords: Antiviral; Mayaro fever; Mayaro virus; Natural and synthetic compounds; Viral targets.

Fig. 1

Schematic structure of MAYV virion. Electron microscopy data show that the viral particle is about 70 nm in diameter. The virion is composed of a positive single-stranded RNA with an icosahedral capsid formed by the capsid protein (C), covered by an envelope membrane inserted of the E1, E2, and E3 glycoproteins. The E3 protein is not shown since it detaches from the E2 protein at the viral surface during maturation (Ribeiro-Filho et al. 2021). Viral structure was based on Cryo-EM structure of mature MAYV (PDB ID: 7KO8) (Ribeiro-Filho et al. 2021)

Fig. 2

Schematic representation of MAYV replicative cycle. The replicative cycle and genomic structure of MAYV. E envelope, nsP nonstructural protein, UTR untranslated region, nt nucleotides. MAYV attaches to the host cells through the interaction between the host receptors and glycoproteins. Endocytosis occurs through a clathrin-coated pit or, alternatively, a caveolin-coated pit; virus internalization starts after interaction with host cell receptors; the low pH in the endosome leads to structural modifications in the viral envelope that reveal the E1. The latter mediates cell membrane-virus fusion, and later, endosomal cell membrane-virus fusion. Viral uncoating results in the release of the viral genome, and the replication stage occurs (translation and transcription). From the RNA of the virus, nsP precursors are generated; the replication complex is obtained from nsP proteins. This complex thus allows the synthesis of a minus-strand RNA, and it is used as the template to generate both genomic and subgenomic RNAs. Polyprotein precursor is cleaved by an autoproteolytic serine protease; and genomic RNA involved in nucleocapsid core assembly and genomic RNA packaging. Maturation of glycoproteins pE2 and E1 occurs. In the Golgi, processed glycoproteins are associated. Then they are transported into the cell membrane. At the cell membrane, the pE2 is split into E2 and E3; there is also the association of the viral RNA with the capsid C and the recruitment of E1 allows viral assembly. Last, particles of MAYV associated with the core are released outside of the host cell through the membrane. Compounds with antiviral activity against MAYV are indicated in each step of the virus replication cycle: (i) Viral Entry; (ii) Post-Entry (Maturation, RNA and Protein Synthesis); and (iii) Protective Effect on Host Cells. Viral cycle was based on the work of Diagne and colleagues (Diagne et al. 2020)

Fig. 3

Schematic structure of MAYV glycoprotein. The glycoproteins E1 and E2 interact forming a dimeric unit (A), that is further associated to two additional dimeric units to form a trimer (B). The localization of the trimers is demonstrated in (C), and a diagram of the E1–E2 trimer is shown in (D). The interaction between the glycoproteins and the MRXA8 receptor in host cells is demonstrated in E. MAYV E1 and E2 structure were based on Cryo-EM structure of mature MAYV (PDB ID: 7KO8) (Ribeiro-Filho et al. 2021), and the receptor was based on human MXRA8 (PDB ID: 6JO8) (Powell et al. 2020)

Fig. 4

Schematic structure of MAYV genome and the crystal structure of nsP3 macrodomain and nsP4. Nsp3 is a modular protein with three domains: the N-terminal macro domain, a central zinc-binding domain, and the C-terminal hypervariable domain, being the macro domain constituted by four alpha-helices and six beta-strands. The nsP4 protein acts as an RNA-dependent RNA polymerase (RdRp), and its structure is composed of fingers, the palm containing the GDD active site, and thumb domains. Since RdRp crystal structure of MAYV has not been determined and characterized yet, the template used in the figure was obtained from Ross River virus RdRp (PDB ID: 7F0S) (Tan et al. 2022). The nsP3 structure was based on MAYV macro domain structure (PDB ID: 5IQ5) (Tsika et al. 2019)